Sexual transmission is the major mode of human immunodeficiency virus type 1 (HIV-1) infection worldwide. With the epidemic still raging in many parts of the world, there is an urgent need to develop safe, topically applied microbicides that can efficiently reduce sexually transmitted HIV-1 infection. Cellulose acetate phthalate (CAP), an "inactive" pharmaceutical excipient commonly used in the production of enteric tablets and capsules, has been shown to possess many of the desirable features of a microbicide for HIV-1. In order to bring CAP towards clinical application, a film in which the active ingredient CAP is an integral structural component has been developed. In the presence of water, the film is dispersed and converted into a gel containing micronized CAP that rapidly inactivates HIV and other STD pathogens. The unique dispersible virucidal CAP film is amenable to mass scale industrial production, and avoids disposal and other problems associated with gels. Therefore, In viva safety, distribution and protective efficacy studies are warranted for this promising candidate microbicide formulation. Additionally, CAP film constitutes a convenient tool for delivery of other anti-HIV compounds. In combination with candidate microbicides having a mechanism of action distinct from that of CAP, increased efficacy against sexual transmission of HIV-1 might be achieved. Zinc finger (ZnF) and reverse transcriptase (RT) inhibitors are potential candidates. As part of the development of the CAP film as a candidate microbicide, and to test the hypothesis that microbicide combinations can enhance therapeutic potency, we propose to conduct detailed irritation (Specific Aim # 1) and distribution (Specific Aim #2) studies in rhesus macaques and to determine the protective effect conferred by CAP and combination films against vaginal challenge with CXCR4 and CCR5 utilizing simian-human immunodeficiency viruses (Specific Aim #3). Results from the proposed studies should establish the safety as well as efficacy of CAP and combination candidate microbicide films in an animal model of HIV-1 infection.